1. Field of the Invention
The present invention relates generally to the fields of organic chemistry and antibacterial agents. More particularly, it concerns preparation of hydrophobically enhanced aminoglycosides, such as aminoglycoside-lipid conjugates, and methods of treating antibacterial infections with these aminoglycosides.
2. Description of the Related Art
Aminoglycoside antibiotics constitute a large family of clinically important drugs used in the treatment of bacterial infections (Umezawa and Hooper, 1982). They effect their antibacterial activity by interfering with ribosomal function (via binding to rRNA), which ultimately results in the disruption of protein biosynthesis (Moazed and Noller, 1987; Purohit and Stern, 1994). Aminoglycoside antibiotics present a wide spectrum of action and are effective against most Gram-negative bacteria and certain Gram-positive bacteria. Many of them, e.g., amikacin, gentamicin, kanamycin, neomycin, netilmycin, streptomycin, and tobramycin, have been used clinically for decades as potent antimicrobial agents (Begg and Carclay, 1995). Other analogs, e.g., hygromycin A and spectinomycin, are used frequently as animal medicines in veterinary and agricultural applications (Biehl, 1986; Nakagawa et al., 1987; Schwarz et al., 2004).
Although aminoglycoside antibiotics exhibit potent bactericidal activity, their widespread use has been compromised by dose-related nephrotoxicity and ototoxicity (Mingeot-Leclerq and Tulkens, 1999; Mingeot-Leclerq et al., 1999). Furthermore, as with other antibiotic regimens, their use as the primary treatment of life threatening infections has also been curtailed due to the rapid emergence of resistant strains of bacteria (Neu, 1992; Hayes and Wolf, 1990; Jacoby et al., 1991). Indeed, the explosive growth of multi-drug resistant (MDR) bacteria in hospitals and the community has led to an emerging crisis where an increasing number of antibiotics cease to be of clinical usefulness (Neu, 1992). Despite this growing concern, only one new class of antibiotics, the oxazolidinones, has entered the clinic during the past two decades (Walsh, 2000). As a result, there is a pressing need for novel classes of antibacterial agents with reduced resistance.